Project Summary/Abstract Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. Thus, we seek to follow a group of adults ranging in age from 20-40 years over a 5 year period of time to identify age and dementia-associated changes in cognition and in particular focus on frontal lobe function. Our aims are four-fold. Aim 1 will cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years. Aim 2 will use magnetic resonance imaging to measure white matter integrity on an annual basis in longitudinally followed people. Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changes to identify biomarkers of AD development and that are also correlated with cognition. Aim 4 will study archived and new autopsy brain samples from DS adults to identify molecular pathways that change prior and during AD development. The outcomes of the proposed studies will contribute to the development of noninvasive biomarkers that will assist in early AD diagnosis in DS and monitor disease progression. Further, novel biomarkers that are mechanistically related to aging, AD neuropathology and dementia will also provide outcomes for the design of future therapeutic clinical trials to treat or prevent dementia in DS.